Levofloxacin aldehyde acetal 4-aryl thiosemicarbazide derivatives and its preparation method and application

A technology of levofloxacin and levofloxacin hydrazide, applied in the fields of new drug discovery and innovative drug synthesis

Inactive Publication Date: 2018-11-23
ZHENGZHOU UNIV OF IND TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, most of the aldehydes or ketones used to construct thiosemicarbazone molecules are common benzenes or heterocyclic aromatic aldehydes and ketones, while quinoline aldehydes, especially thiosemicarbazones formed by fluoroquinolinone aldehydes, are currently Not yet reported

Method used

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  • Levofloxacin aldehyde acetal 4-aryl thiosemicarbazide derivatives and its preparation method and application
  • Levofloxacin aldehyde acetal 4-aryl thiosemicarbazide derivatives and its preparation method and application
  • Levofloxacin aldehyde acetal 4-aryl thiosemicarbazide derivatives and its preparation method and application

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Experimental program
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Embodiment 1

[0034] (S)-6-fluoro-7-(4-methyl-piperazin-1-yl)-1,8-(2,1-oxopropyl)-quinolin-4(1H)-one-3- Aldehyde 4-phenylthiosemicarbazide (I-1), its chemical structural formula is:

[0035]

[0036] That is, Ar in formula I is a benzene ring.

[0037] The preparation method of this compound is: levofloxacin aldehyde crude product (1.0g) shown in formula IV is dissolved in absolute ethanol (30 milliliters), adds 4-phenylthiosemicarbazide (0.6g, 3.6mmol) shown in formula VIII, Reflux for 12 hours, filter while hot, wash 2 times with ethanol, wash the solid twice with distilled water successively, dry, and recrystallize with DMF-ethanol (V:V=5:3) mixed solvent to obtain light yellow crystals of formula (I -1), obtain product 0.63g, m.p.234~236 ℃. 1 H NMR (400MHz, DMSO-d 6 ): 11.76(s, 1H, CH=N), 9.95(s, 1H, NH), 8.87(s, 1H, 2-H), 8.45(s, 1H, NH), 7.62~7.25(m, 6H, Ph-H and5-H),4.61~4.34(m,3H,OCH 2 CH), 3.24(t, 4H, piperazine-H), 2.45(t, 4H, piperazine-H), 2.23(s, 3H, N-CH 3 ), 1.45 (d,...

Embodiment 2

[0039] (S)-6-fluoro-7-(4-methyl-piperazin-1-yl)-1,8-(2,1-oxopropyl)-quinolin-4(1H)-one-3- Aldehyde 4-(4-methylphenyl) thiosemicarbazide (I-2), its chemical structural formula is:

[0040]

[0041] That is, Ar in formula I is 4-methylphenyl.

[0042]The preparation method of this compound is: levofloxacin aldehyde crude product (1.0g) shown in formula IV is dissolved in absolute ethanol (30 milliliters), adds 4-(4-methylphenyl) thiosemicarbazide (0.6g) shown in formula VIII ,3.3mmol), reflux reaction for 10 hours, filtered while hot, the solid was washed twice with ethanol and distilled water twice, dried, and recrystallized with a mixed solvent of DMF-ethanol (V:V=5:3) to obtain light yellow Crystalline formula (I-2), 0.58g of the product was obtained, m.p.227-229°C. 1 H NMR (400MHz, DMSO-d 6 ): 11.77(s, 1H, CH=N), 9.86(s, 1H, NH), 8.91(s, 1H, 2-H), 8.44(s, 1H, NH), 8.25~7.46(m, 5H, Ph-H and5-H),4.63~4.35(m,3H,OCH 2 CH), 3.24(t, 4H, piperazine-H), 2.42(t, 4H, piperazin...

Embodiment 3

[0044] (S)-6-fluoro-7-(4-methyl-piperazin-1-yl)-1,8-(2,1-oxopropyl)-quinolin-4(1H)-one-3- Aldehyde 4-(4-methoxyphenyl) thiosemicarbazide (I-2), its chemical structural formula is:

[0045]

[0046] That is, Ar in formula I is 4-methoxyphenyl.

[0047] The preparation method of this compound is: levofloxacin aldehyde crude product (1.0g) shown in formula IV is dissolved in dehydrated alcohol (30 milliliters), adds 4-(4-methoxyphenyl) thiosemicarbazide shown in formula VIII ( 0.7g, 3.6mmol), reflux reaction for 10 hours, filtered while hot, the solid was washed twice with ethanol and distilled water twice, dried, and recrystallized with DMF-ethanol (V:V=5:3) mixed solvent to obtain Pale yellow crystal formula (I-3), 0.65 g of the product, m.p.235-237°C. 1 H NMR (400MHz, DMSO-d 6 ): 11.75(s, 1H, CH=N), 9.87(s, 1H, NH), 8.87(s, 1H, 2-H), 8.43(s, 1H, NH), 7.48~6.95(m, 5H, Ph-H and5-H),4.58~4.33(m,3H,OCH 2 CH), 3.78(s,3H,OCH 3 ), 3.24(t, 4H, piperazine-H), 2.45(t, 4H, piper...

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Abstract

The invention discloses levofloxacin aldehyde 4-arylthiosemicarbazone derivatives. The levofloxacin aldehyde 4-arylthiosemicarbazone derivatives have a general structural formula shown in the description, wherein in the formula, a substituent Ar represents a phenyl ring, a substituted phenyl ring, a pyridine ring, a furan ring or a thiophene ring. The invention also discloses a preparation method and application of the levofloxacin aldehyde 4-arylthiosemicarbazone derivatives. The levofloxacin aldehyde 4-arylthiosemicarbazone derivatives realize splicing of three dominant pharmacophores such as a chiral fluoroquinolone skeleton, Schiff base imine and thiourea so that anti-tumor activity of the novel compound is improved and toxic or side effects on normal cells are reduced. The levofloxacin aldehyde 4-arylthiosemicarbazone derivatives can be used as anti-tumor active substances to develop a novel-structure anti-tumor drug.

Description

technical field [0001] The invention belongs to the technical field of new drug discovery and innovative drug synthesis, and specifically relates to a levofloxacin aldehyde 4-aryl thiosemicarbazide derivative, a preparation method thereof, and an application thereof in antitumor drugs. Background technique [0002] The innovation of new drugs originates from the discovery of leads, and the construction of lead molecules based on the combination of dominant pharmacophore skeletons is the most economical and effective strategy. The thiosemicarbazone derivatives constructed from aldehydes or ketones and thiosemicarbazides have attracted much attention because they are easy to form complexes or chelate with macromolecules or metal ions, and exhibit a wide range of pharmacological activities. However, most of the aldehydes or ketones used to construct thiosemicarbazone molecules are common benzenes or heterocyclic aromatic aldehydes and ketones, while quinoline aldehydes, especia...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D498/06A61K31/5383A61P35/00A61P35/02
CPCC07D498/06
Inventor 李珂李星陈百泉姜亚玲胡国强
Owner ZHENGZHOU UNIV OF IND TECH
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